Unpublished data from the inventors evidences that Ambroxol is a powerful inducer of autophagy. However, its plasma half-life in humans is only 3.72 hours (1) meaning multiple doses daily need to be given in order to provide an effective concentration. Its major route of elimination is via urinary excretion of a glucuronide (2) conjugate, so any other factors are not predicted to alter metabolism or tissue pharmacokinetics or dynamics.
Ambroxol's major metabolism by human microsomes was shown to be by cyp3A4 mediated oxidation to dibromoanthranilic acid (DBAA).(3) See FIG. 1. Thus, any potential use of ambroxol in treating diseases autophagy-mediated disease states and/or conditions like tuberculosis (TB) may be greatly compromised by the cyp3A4 inducing nature of many TB medicines such as rifampin. Alternatively, the use of cyp3A4 inhibiting medications with ambroxol may also lead to greater than desired levels of ambroxol because it is no longer being metabolized by cyp3A4. Thus, unfortunately, the inherent susceptibility of ambroxol to cyp3A4 will make it difficult to dose in humans in diseases such as TB treated with rifampin or other anti-TB agents, or when cyp3A4 inhibiting compounds are given.
Furthermore, ambroxol displays lung concentrating effects that will potentiate its effects in lung diseases such as tuberculosis. It is rarely acknowledged that lung tissues express significant cyp3A4, as well as the more commonly understood liver expression, and cyp3A4 is found in human lungs in sites including bronchial glands, bronchiolar columnar and terminal epithelium, type II alveolar epithelium, and alveolar macrophages.(4) Therefore, even if ambroxol is given in inhaled forms, it will inherently and unexpectedly be metabolized into inactive forms by lung tissue cyp3A4 limiting lung exposure levels to ambroxol.